PainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways is defined as an unpleasant sensorySensoryNeurons which conduct nerve impulses to the central nervous system.Nervous System: Histology and emotional experience associated with actual or potential tissue damage. PainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways is a subjective experience. Acute painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways lasts < 3 months and typically has a specific, identifiable cause. Chronic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways lasts > 3 months and may exist in the absence of tissue damage or after healing would have been expected to occur. PainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways management involves a combination of addressing underlying causes and using a systematic approach tailored to the clinical scenario.
NociceptionNociceptionSensing of noxious mechanical, thermal or chemical stimuli by nociceptors. It is the sensory component of visceral and tissue pain (nociceptive pain).Pain: Types and Pathways: process through which peripheral receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors transmit information about current (or potential) tissue damage centrally as painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
NociceptorNociceptorPeripheral afferent neurons which are sensitive to injuries or pain, usually caused by extreme thermal exposures, mechanical forces, or other noxious stimuli. Their cell bodies reside in the dorsal root ganglia. Their peripheral terminals (nerve endings) innervate target tissues and transduce noxious stimuli via axons to the central nervous system.Pain: Types and Pathways: receptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors in end-organ that detects biochemical changes associated with current or potential tissue damage
Nociceptive painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways: painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways caused by actual or threatened damage to non-neural tissue
Neuropathic painNeuropathic painCaused by lesion or disease affecting the nervous system (PNS or CNS).Pain: Types and Pathways: painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways caused by pathology in the somatosensory nervous systemNervous systemThe nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system.Nervous System: Anatomy, Structure, and Classification
Peripheral sensitization:painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways perceived at a lower thresholdThresholdMinimum voltage necessary to generate an action potential (an all-or-none response)Skeletal Muscle Contraction of peripheral nociceptive stimulation and/or an increase in painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and PathwaysperceptionPerceptionThe process by which the nature and meaning of sensory stimuli are recognized and interpreted.Psychiatric Assessment at a given level of peripheral nociceptive stimulation
Central sensitizationCentral sensitizationIncreased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold input.Pain: Types and Pathways: increased responsiveness of nociceptive neuronsNeuronsThe basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system.Nervous System: Histology in the central nervous systemCentral nervous systemThe main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges.Nervous System: Anatomy, Structure, and Classification to normal or subthreshold input
Allodynia: painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways due to a stimulus that does not typically provoke painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
HyperalgesiaHyperalgesiaAn increased sensation of pain or discomfort produced by minimally noxious stimuli due to damage to soft tissue containing nociceptors or injury to a peripheral nerve.Pain: Types and Pathways/hyperpathia: heightened response to a typically painful stimuli
Physiology
Complex bidirectional process with phases:
TransductionTransductionThe transfer of bacterial DNA by phages from an infected bacterium to another bacterium. This also refers to the transfer of genes into eukaryotic cells by viruses. This naturally occurring process is routinely employed as a gene transfer technique.Bacteriology
Transmission
Modulation
Central perceptionPerceptionThe process by which the nature and meaning of sensory stimuli are recognized and interpreted.Psychiatric Assessment
Peripheral nervesPeripheral NervesThe nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium.Nervous System: Histology, both motorMotorNeurons which send impulses peripherally to activate muscles or secretory cells.Nervous System: Histology and sensorySensoryNeurons which conduct nerve impulses to the central nervous system.Nervous System: Histology, are grouped by size and myelination.
PainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways is experienced in 2 phases:
1st phase is mediated by the fast-conducting A-delta fibers, associated with an initial sharp painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways (fast painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways).
2nd phase is mediated by C fibers, associated with a more prolonged and a less intense feeling of painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways (slow, sustained painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways).
Primary receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors of the muscle spindle and Golgi tendon organ
Secondary receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors of the muscle spindle, contribute to cutaneous mechanoreceptors
Free nerve endings that conduct stimuli related to pressure and temperature
Action potentialAction PotentialAbrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli.Membrane Potential conducts at a rate of approximately 20 m/s towards the central nervous systemCentral nervous systemThe main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges.Nervous System: Anatomy, Structure, and Classification (CNS)
A gamma:
MotorMotorNeurons which send impulses peripherally to activate muscles or secretory cells.Nervous System: HistologyneuronsNeuronsThe basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system.Nervous System: Histology that control the intrinsic activation of the muscle spindle
Do not transmit signals that contribute to painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways under normal conditions (but may in the pathologic state of central sensitizationCentral sensitizationIncreased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold input.Pain: Types and Pathways)
Unmyelinated nociceptive slow fibers (conduct at a rate of approximately 2 m/s)
Respond to combinations of thermal, mechanical, and chemical nociceptive stimuli
The 4 processes that make up nociception: transduction, transmission, modulation, and perception
Image by Lecturio.
Types of Pain
Types of painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways according to duration
Type
Duration
Characteristic
Acute painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
< 3 months
Usually related to tissue damage
Improves with resolution of injury
Associated with autonomic protective reflexes (e.g., muscle spasm or “splinting”)
Chronic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
> 3 months
PainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways that extends beyond expected period of healing
Pathology usually insufficient to explain the presence or extent of the painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
Disrupts sleepSleepA readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility.Physiology of Sleep, daily activities, and psychosocial function
Types of painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways according to qualityQualityActivities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps.Quality Measurement and Improvement
Type
Duration
Characteristic
Nociceptive painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
Typically acute
The result of direct stimulation of nociceptorsNociceptorsPeripheral afferent neurons which are sensitive to injuries or pain, usually caused by extreme thermal exposures, mechanical forces, or other noxious stimuli. Their cell bodies reside in the dorsal root ganglia. Their peripheral terminals (nerve endings) innervate target tissues and transduce noxious stimuli via axons to the central nervous system.Pain: Types and Pathways and normal neural signaling to the brainBrainThe part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem.Nervous System: Anatomy, Structure, and Classification
May be due to tissue damage or threat of potential damage at the nociceptorNociceptorPeripheral afferent neurons which are sensitive to injuries or pain, usually caused by extreme thermal exposures, mechanical forces, or other noxious stimuli. Their cell bodies reside in the dorsal root ganglia. Their peripheral terminals (nerve endings) innervate target tissues and transduce noxious stimuli via axons to the central nervous system.Pain: Types and Pathways
Characteristics vary based on nociceptorNociceptorPeripheral afferent neurons which are sensitive to injuries or pain, usually caused by extreme thermal exposures, mechanical forces, or other noxious stimuli. Their cell bodies reside in the dorsal root ganglia. Their peripheral terminals (nerve endings) innervate target tissues and transduce noxious stimuli via axons to the central nervous system.Pain: Types and Pathways type/location
Somatic: easy to localize, perceived by nociceptorsNociceptorsPeripheral afferent neurons which are sensitive to injuries or pain, usually caused by extreme thermal exposures, mechanical forces, or other noxious stimuli. Their cell bodies reside in the dorsal root ganglia. Their peripheral terminals (nerve endings) innervate target tissues and transduce noxious stimuli via axons to the central nervous system.Pain: Types and Pathways located on the skinSkinThe skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue.Skin: Structure and Functions or in musculoskeletal tissues (e.g., fractureFractureA fracture is a disruption of the cortex of any bone and periosteum and is commonly due to mechanical stress after an injury or accident. Open fractures due to trauma can be a medical emergency. Fractures are frequently associated with automobile accidents, workplace injuries, and trauma.Overview of Bone Fractures, burnsBurnsA burn is a type of injury to the skin and deeper tissues caused by exposure to heat, electricity, chemicals, friction, or radiation. Burns are classified according to their depth as superficial (1st-degree), partial-thickness (2nd-degree), full-thickness (3rd-degree), and 4th-degree burns. Burns)
Visceral: poorly localized, perceived by nociceptorsNociceptorsPeripheral afferent neurons which are sensitive to injuries or pain, usually caused by extreme thermal exposures, mechanical forces, or other noxious stimuli. Their cell bodies reside in the dorsal root ganglia. Their peripheral terminals (nerve endings) innervate target tissues and transduce noxious stimuli via axons to the central nervous system.Pain: Types and Pathways found in organ systems (e.g., pancreatitisPancreatitisInflammation of the pancreas. Pancreatitis is classified as acute unless there are computed tomographic or endoscopic retrograde cholangiopancreatographic findings of chronic pancreatitis. The two most common forms of acute pancreatitis are alcoholic pancreatitis and gallstone pancreatitis.Acute Pancreatitis, myocardial infarctionMyocardial infarctionMI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms.Myocardial Infarction)
VariableVariableVariables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups.Types of Variables, often chronic
Due to nerve damage or aberrant painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways processing
Described as burning, tinglingTinglingPosterior Cord Syndrome, or shock-like, distributed along the path of nerves or nerve roots
Usually presents with hyperpathia, allodynia, and sensorySensoryNeurons which conduct nerve impulses to the central nervous system.Nervous System: Histology deficit
Examples: painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways associated with herpetic neuralgia, sciatica, neoplasias, diabetic neuropathyDiabetic neuropathyPeripheral, autonomic, and cranial nerve disorders that are associated with diabetes mellitus. These conditions usually result from diabetic microvascular injury involving small blood vessels that supply nerves (vasa nervorum). Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; a painful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy.Chronic Diabetic Complications, phantom painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways, etcETCThe electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP).Electron Transport Chain (ETC).
Nociplastic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways (recently defined)
Usually chronic or intermittent
Altered nociceptionNociceptionSensing of noxious mechanical, thermal or chemical stimuli by nociceptors. It is the sensory component of visceral and tissue pain (nociceptive pain).Pain: Types and Pathways despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptorsNociceptorsPeripheral afferent neurons which are sensitive to injuries or pain, usually caused by extreme thermal exposures, mechanical forces, or other noxious stimuli. Their cell bodies reside in the dorsal root ganglia. Their peripheral terminals (nerve endings) innervate target tissues and transduce noxious stimuli via axons to the central nervous system.Pain: Types and Pathways or evidence for disease or lesion of the somatosensory system causing the painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
Examples: fibromyalgiaFibromyalgiaFibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia, complex regional pain syndromeComplex Regional Pain SyndromeComplex regional pain syndrome (CRPS) is a chronic regional neuropathic pain condition characterized by excruciating pain (out of proportion to apparent tissue damage or inciting trauma), paresthesia, allodynia, temperature abnormalities, skin discoloration, edema, reduced range of motion, and bone demineralization. Complex Regional Pain Syndrome (CRPS), chronic low back painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways, irritable bowel syndromeIrritable bowel syndromeIrritable bowel syndrome (IBS) is a functional bowel disease characterized by chronic abdominal pain and altered bowel habits without an identifiable organic cause. The etiology and pathophysiology of this disease are not well understood, and there are many factors that may contribute. Irritable Bowel Syndrome, bladderBladderA musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination.Pyelonephritis and Perinephric AbscesspainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways syndrome
Management of Pain
General principles
Must be tailored to each patient’s circumstances, perspective, and physiologic condition
Requires a systematic assessment and regularRegularInsulin reassessments:
Type: throbbing, cramping, burning, stabbing, etcETCThe electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP).Electron Transport Chain (ETC).
Periodicity: continuous, with or without exacerbations or incident
Whenever possible, use targeted, disease-specific treatment.
Incorporate non-pharmacologic adjuncts and maximize the use of non-opioid analgesics before the use of opioidsOpioidsOpiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics.
If an opioidOpioidCompounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis.Constipation is prescribed for painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways:
OpioidOpioidCompounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis.Constipation Risk Tool (ORT)
Utilize local prescription monitoring program
Counsel patientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship on safe storage and disposal
Management of chronic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
The following principles are recommended by the World Health Organization (WHO) as a basis for the treatment of chronic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways:
“By the clock”: Analgesics should be given at regular intervals. The frequency depends on whether it is a long- or short-acting preparation.
“By the mouth”: If possible, drugs should be administered orally. If the oral route is not feasible, the least invasive route should be considered (e.g., sublingual or subcutaneous before IV).
“By the ladder”: Stick to the 3-step system (see figure below). Drug selection should be appropriate to the severity of the pain. With severe pain, it may be appropriate to begin at the top of the ladder with a strong opioid. It is usually not necessary to step down unless the cause of pain is believed to have resolved.
“By the individual with attention to details”: Dosing of painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways medication should be adapted to the individual, as every patient responds differently. To optimize adherence and outcomes, the patient and those who care for them should be provided with a written program.
AcetaminophenAcetaminophenAcetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood.Acetaminophen
AspirinAspirinThe prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis.Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Weak opioidsOpioidsOpiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
CodeineCodeineAn opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough.Opioid Analgesics
Dihydrocodeine
TramadolTramadolA narcotic analgesic proposed for severe pain. It may be habituating.Opioid Analgesics
Strong opioidsOpioidsOpiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
MorphineMorphineThe principal alkaloid in opium and the prototype opiate analgesic and narcotic. Morphine has widespread effects in the central nervous system and on smooth muscle.Opioid Analgesics
MethadoneMethadoneA synthetic opioid that is used as the hydrochloride. It is an opioid analgesic that is primarily a mu-opioid agonist.Opioid Analgesics
HydromorphoneHydromorphoneAn opioid analgesic made from morphine and used mainly as an analgesic. It has a shorter duration of action than morphine.Opioid Analgesics
Oxymorphone
BuprenorphineBuprenorphineA derivative of the opioid alkaloid thebaine that is a more potent and longer lasting analgesic than morphine. It appears to act as a partial agonist at mu and kappa opioid receptors and as an antagonist at delta receptors. The lack of delta-agonist activity has been suggested to account for the observation that buprenorphine tolerance may not develop with chronic use.Opioid Analgesics
FentanylFentanylA potent narcotic analgesic, abuse of which leads to habituation or addiction. It is primarily a mu-opioid agonist. Fentanyl is also used as an adjunct to general anesthetics, and as an anesthetic for induction and maintenance.Opioid Analgesics
AdjuvantAdjuvantSubstances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity.Vaccination analgesics (for specific indications)
Alpha-2 adrenergic agonistsAdrenergic agonistsSympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (î±, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate).Sympathomimetic Drugs (e.g., clonidineClonidineAn imidazoline sympatholytic agent that stimulates alpha-2 adrenergic receptors and central imidazoline receptors. It is commonly used in the management of hypertension.Sympathomimetic Drugs, tizanidineTizanidineSpasmolytics):
Augment the effect of opioidsOpioidsOpiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
Allow for reduction of opioidOpioidCompounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis.Constipation dosages in acute postoperative painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways, chronic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways, neuropathic painNeuropathic painCaused by lesion or disease affecting the nervous system (PNS or CNS).Pain: Types and Pathways
Anticonvulsants (e.g., gabapentinGabapentinA cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of partial seizures; neuralgia; and restless legs syndrome.Second-Generation Anticonvulsant Drugs, phenytoinPhenytoinAn anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.First-Generation Anticonvulsant Drugs, carbamazepineCarbamazepineA dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties.First-Generation Anticonvulsant Drugs, pregabalinPregabalinA gamma-aminobutyric acid (gaba) derivative that functions as a calcium channel blocker and is used as an anticonvulsant as well as an anti-anxiety agent. It is also used as an analgesic in the treatment of neuropathic pain and fibromyalgia.Second-Generation Anticonvulsant Drugs):
Primarily used in neuropathic painNeuropathic painCaused by lesion or disease affecting the nervous system (PNS or CNS).Pain: Types and Pathways syndromes (e.g., trigeminal neuralgiaTrigeminal neuralgiaTrigeminal neuralgia (TN) is an often chronic and recurring pain syndrome involving the sensory distribution of the trigeminal nerve (cranial nerve (CN) V). The pain is typically unilateral and described as an acute, sharp, electric-shock-like pain involving the maxillary or mandibular areas and often associated with spasm of facial muscles. Trigeminal Neuralgia, peripheral neuropathyPeripheral NeuropathyNeurofibromatosis Type 2)
May be useful as adjuvants in chronic nociceptive painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways syndromes (e.g., osteoarthritisOsteoarthritisOsteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis)
May be used as migraineMigraineMigraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine HeadacheheadacheHeadacheThe symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders.Brain AbscessprophylaxisProphylaxisCephalosporins
Antidepressants (e.g., tricyclics, serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS–norepinephrineNorepinephrinePrecursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus.Receptors and Neurotransmitters of the CNS reuptake inhibitors (SNRIsSNRIsSerotonin Reuptake Inhibitors and Similar Antidepressants)):
Primarily used in neuropathic painNeuropathic painCaused by lesion or disease affecting the nervous system (PNS or CNS).Pain: Types and Pathways syndromes (e.g., trigeminal neuralgiaTrigeminal neuralgiaTrigeminal neuralgia (TN) is an often chronic and recurring pain syndrome involving the sensory distribution of the trigeminal nerve (cranial nerve (CN) V). The pain is typically unilateral and described as an acute, sharp, electric-shock-like pain involving the maxillary or mandibular areas and often associated with spasm of facial muscles. Trigeminal Neuralgia, peripheral neuropathyPeripheral NeuropathyNeurofibromatosis Type 2)
May be used as migraineMigraineMigraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine HeadacheheadacheHeadacheThe symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders.Brain AbscessprophylaxisProphylaxisCephalosporins
Beta-blockersBeta-blockersDrugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.Class 2 Antiarrhythmic Drugs (Beta Blockers) (metopropolol, propanolol, timololTimololA beta-adrenergic antagonist that is similar in action to propranolol; the levo-isomer is more active. Timolol has been proposed as an anti-hypertensive, anti-arrhythmic, anti-angina, and anti-glaucoma agent. It is also used in the treatment of migraine disorders and tremor.Class 2 Antiarrhythmic Drugs (Beta Blockers)): may be used as migraineMigraineMigraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine HeadacheheadacheHeadacheThe symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders.Brain AbscessprophylaxisProphylaxisCephalosporins
BisphosphonatesBisphosphonatesBisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix “-dronate” or “-dronic acid” (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption.Bisphosphonates: may be used to treat cancer-related boneBoneBone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and TypespainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways, osteoarthritisOsteoarthritisOsteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis
Botulinum toxinBotulinum toxinToxic proteins produced from the species Clostridium botulinum. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon endocytosis into presynaptic nerve endings. Once inside the cell the botulinum toxin light chain cleaves specific snare proteins which are essential for secretion of acetylcholine by synaptic vesicles. This inhibition of acetylcholine release results in muscular paralysis.Botulism:
May be used to treat muscle spasticityMuscle spasticityA form of muscle hypertonia associated with upper motor neuron disease. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a ‘free interval’) followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by hyperreflexia and variable degrees of muscle weakness.Motor Neuron Lesions → decreased spasticity-related painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
May be used to treat bruxism → decreased temporomandibular joint (TMJ)–related painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
May be used as migraineMigraineMigraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine HeadacheheadacheHeadacheThe symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders.Brain AbscessprophylaxisProphylaxisCephalosporins
Cannabis and cannabinoidsCannabinoidsCannabinoids are a class of compounds interacting with cannabinoid receptors. The 3 types of cannabinoids are phytocannabinoids (naturally derived from flora), endocannabinoids (endogenous), and synthetic cannabinoids (artificially produced). Cannabinoids (e.g., nabiximols, dronabinolDronabinolA psychoactive compound extracted from the resin of cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (thc) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound.Cannabinoids, nabiloneNabiloneCannabinoids):
Primarily used in cancer painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways syndromes
Some evidence of efficacy in neuropathic painNeuropathic painCaused by lesion or disease affecting the nervous system (PNS or CNS).Pain: Types and Pathways syndromes
Used as a short-term, potent antiinflammatory in several painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways syndromes
Used in the neurosurgical setting to treat headacheHeadacheThe symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders.Brain Abscess caused by increased intracranial pressureIncreased Intracranial PressureNormal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption.Increased Intracranial Pressure (ICP)
Used in the oncology setting to treat cancer-related boneBoneBone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and TypespainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
N-methyl-D-aspartate (NMDA) receptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors antagonists (ketamineKetamineA cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (n-methyl-d-aspartate receptors) and may interact with sigma receptors.Intravenous Anesthetics):
Primarily used as an adjuvantAdjuvantSubstances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity.Vaccination to treat perioperative painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
Some evidence of efficacy in neuropathic painNeuropathic painCaused by lesion or disease affecting the nervous system (PNS or CNS).Pain: Types and Pathways syndromes
Topical agents (e.g., lidocaineLidocaineA local anesthetic and cardiac depressant used as an antiarrhythmic agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine.Local Anesthetics, capsaicin, diclofenacDiclofenacA non-steroidal anti-inflammatory agent (nsaid) with antipyretic and analgesic actions. It is primarily available as the sodium salt.Nonsteroidal Antiinflammatory Drugs (NSAIDs)patchPatchNonpalpable lesion > 1 cm in diameterGeneralized and Localized Rashes, ketamineKetamineA cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (n-methyl-d-aspartate receptors) and may interact with sigma receptors.Intravenous Anesthetics cream, gabapentinGabapentinA cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of partial seizures; neuralgia; and restless legs syndrome.Second-Generation Anticonvulsant Drugs cream): may be used to treat regional neuropathic painNeuropathic painCaused by lesion or disease affecting the nervous system (PNS or CNS).Pain: Types and Pathways
Approach to specific types of painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
Nociceptive painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
Ideal treatment: Remove underlying cause (initial analgesics should be administered in
tandem with diagnostic testsDiagnostic testsDiagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests).
Pharmacologic therapy follows the WHO 3-step approach involving non-opioid analgesics,
mild opioidsOpioidsOpiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, and strong opioidsOpioidsOpiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics, with or without adjuvants.
1st step: non-opioid analgesics (NSAIDsNSAIDSPrimary vs Secondary Headaches, aspirinAspirinThe prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis.Nonsteroidal Antiinflammatory Drugs (NSAIDs), acetaminophenAcetaminophenAcetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood.Acetaminophen). Keep
in mind the ceiling effect of non-opioids (no additional analgesic effect beyond a
certain dose).
2nd step: if non-opioid analgesics are insufficient → opioidOpioidCompounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis.Constipation analgesics
Non-opioid and opioidOpioidCompounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis.Constipation analgesics have additive effects and can be combined.
Must screen for risk of opioidOpioidCompounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis.Constipation use disorder
Long-term opioidOpioidCompounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis.Constipation use is reserved for cancer-related or end-of-life painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways.
In cases of extreme painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways, patient-controlled analgesiaAnalgesiaMethods of pain relief that may be used with or in place of analgesics.Anesthesiology: History and Basic Concepts is used.
In the case of chronic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways, both emotional and organic factors should be assessed before initiating therapy.
AdjuvantAdjuvantSubstances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity.Vaccination therapy options other than traditional analgesics: antidepressants, anticonvulsants
Topical analgesic therapy (e.g., lidocaineLidocaineA local anesthetic and cardiac depressant used as an antiarrhythmic agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine.Local Anesthetics, NSAIDsNSAIDSPrimary vs Secondary Headaches, capsaicin)
Second-line:
OpioidsOpioidsOpiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
NMDA receptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors antagonists (e.g., ketamineKetamineA cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (n-methyl-d-aspartate receptors) and may interact with sigma receptors.Intravenous Anesthetics)
Muscle relaxants (e.g., tizanidineTizanidineSpasmolytics, baclofenBaclofenA gamma-aminobutyric acid derivative that is a specific agonist of gaba-b receptors. It is used in the treatment of muscle spasticity, especially that due to spinal cord injuries. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission.Spasmolytics)
Third-line:
CannabinoidsCannabinoidsCannabinoids are a class of compounds interacting with cannabinoid receptors. The 3 types of cannabinoids are phytocannabinoids (naturally derived from flora), endocannabinoids (endogenous), and synthetic cannabinoids (artificially produced). Cannabinoids
Botulinum toxinBotulinum toxinToxic proteins produced from the species Clostridium botulinum. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon endocytosis into presynaptic nerve endings. Once inside the cell the botulinum toxin light chain cleaves specific snare proteins which are essential for secretion of acetylcholine by synaptic vesicles. This inhibition of acetylcholine release results in muscular paralysis.Botulism
Intrathecal ziconotide
Fourth-line:
Electrical nerve stimulation
Sympathetic nerve blocks
Steroid injections
Non-pharmacological treatments
To be used as a first-line measure or as an adjunct in multimodal painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways management:
Distraction, guided imagery, and/or biofeedbackBiofeedbackThe therapy technique of providing the status of one’s own autonomic nervous system function (e.g., skin temperature, heartbeats, brain waves) as visual or auditory feedback in order to self-control related conditions (e.g., hypertension, migraine headaches).Psychotherapy
Music therapy
Occupational therapyOccupational TherapySkilled treatment that helps individuals achieve independence in all facets of their lives. It assists in the development of skills needed for independent living.Fetal Alcohol Spectrum Disorder
References
Dennis L. Kasper et. al. (2015). Harrison’s Principles of Internal Medicine. Chapter 18: Pain: Pathophysiology and Management, Part 2: Cardinal Manifestations and Presentation of Diseases, Section 1: Pain, page 87–95.
Owen GT, Bruel BM, Schade CM, Eckmann MS, Hustak EC, Engle MP. Evidence-based pain medicine for primary care physicians. Proc (Bayl Univ Med Cent). 2018;31(1):37-47. Published 2018 Jan 8. doi:10.1080/08998280.2017.1400290. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903506/
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